The objective of this proposal, "Transnational Therapies for Malignant Gliomas", is to establish a systematic program of developmental drug and molecular therapeutic studies in adults with malignant gliomas at the Henry Ford Health Sciences Center (HFHSC) which complements the same objective at Case Western Reserve University/Ireland Cancer Center (CWRU/ICC) and the University of Tennessee/Semmes Murphey Clinic (UT/SMC), the combination of which forms the Henry Ford Health Sciences Center Consortium. The developmental drug therapeutics research program will develop and test innovative Phase I and Phase II agents with sound pharmacological rationale. These therapeutic strategies will focus on improving cytotoxic effects by: 1) examining and modifying cell resistance mechanisms, 2) protecting normal tissues from chemotherapy induced systemic toxicity, and 3) combining novel radiation sensitizer and radiotherapy. Specifically, we have studied glutathione, glutathione-S-transferase, MDR-1/p-glycoprotein and metallothionine in relation to tumor cell resistance. We have developed a means to selectively protect normal tissue toxicity from platinum and nitrosourea therapy by increased exposure to the trace metal zinc. Furthermore, we have demonstrated that topotecan acts as a radiation therapy sensitizer. The molecular therapeutics research program will focus on the identification of gene products involved in progression and/or invasion. Four models, both in vitro and in vivo, are currently being developed and validated, including basement membrane, organotypic, spheroid, and intercerebral growth assays. These models will provide the means to 1) dissect the mechanisms of invasion and 2) measure antiinvasive effects of novel inhibitors. Novel tumor suppressor and/or oncogenes identified by molecular approaches will 1) serve as progression markers for diagnostic purposes and 2) be analyzed in tumorigenicity and invasion models. The identification of genes and gene products involved in progression and/or invasion will permit the development of novel antitumor therapies to be tested in further Phase I and Phase II trials. For example, we have identified cysteine proteases (CP) as at least partially responsible for invasion of malignant meningiomas and gliomas. Exposure to specific CP inhibitors has blocked tumor cell invasions in vitro. Preclinical in vivo studies are under way. Tumors from patients in the clinical trials will be studied for the correlation between clinical outcome and cellular mechanisms of underlying cytotoxicity, invasion, and/or progression. We expect the rapid development and completion of clinical trials resulting from the integrated research programs through the coordination of the HFHSC consortium COO/CC.